PT  - JOURNAL ARTICLE
AU  - Vargas-Poussou, Rosa
AU  - Dahan, Karin
AU  - Kahila, Diana
AU  - Venisse, Annabelle
AU  - Riveira-Munoz, Eva
AU  - Debaix, Huguette
AU  - Grisart, Bernard
AU  - Bridoux, Franck
AU  - Unwin, Robert
AU  - Moulin, Bruno
AU  - Haymann, Jean-Philippe
AU  - Vantyghem, Marie-Christine
AU  - Rigothier, Claire
AU  - Dussol, Bertrand
AU  - Godin, Michel
AU  - Nivet, Hubert
AU  - Dubourg, Laurence
AU  - Tack, Ivan
AU  - Gimenez-Roqueplo, Anne-Paule
AU  - Houillier, Pascal
AU  - Blanchard, Anne
AU  - Devuyst, Olivier
AU  - Jeunemaitre, Xavier
TI  - Spectrum of Mutations in Gitelman Syndrome
AID  - 10.1681/ASN.2010090907
DP  - 2011 Apr 01
TA  - Journal of the American Society of Nephrology
PG  - 693--703
VI  - 22
IP  - 4
4099  - http://jasn.asnjournals.org/content/22/4/693.short
4100  - http://jasn.asnjournals.org/content/22/4/693.full
SO  - J. Am. Soc. Nephrol.2011 Apr 01; 22
AB  - Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.